Although the causes of the majority of cases of PD are not known, genetic studies of PD(<10% of total cases of PD) have recently identified two missense mutations (A30P) and (A53T) in alpha-SYN. Moreover, in PD (familial and sporadic) and in Diffuse Lewy Body Disease (DLB), alpha-Syn accumulates in Lewy Bodies (LB), filamentous cytoplasmic inclusions, in subsets of nerve cells. These findings indicate that the alpha-Syn are not known, it is abundant in neurons and is particularly enriched in the presynaptic terminals. In humans and rodents, beta-Syn and gamma-Syn are also expressed in the nervous tissue. To gain better understanding of the role of alpha-Syn biology in the pathogenesis of PD and in the PD- associated degeneration/dysfunction of nigral-striatal dopaminergic system, we will examine the expression and the cell biology of alpha-Syn in the MPTP-intoxication mouse model of PD and in Tg mice expression wild type or mutant (A30P and A53T) Hu alpha-Syn. Specifically, we propose: 1) to generate Tg mice expressing high levels of wild-type or mutant Hu alpha-Syn and to analyze the character/evolution of abnormalities in these mice; 2) to determine whether transport/metabolism of alpha-synuclein is altered by a familial PD-linked mutation in the nigral-striatal system of the Tg mice; 3) to determine whether expression of wild type or mutant Hu alpha-Syn in Tg mice alters sensitivity of dopaminergic neurons to MPTP toxicity; 4) to determine patterns of mRNA expression and protein localization of different Syn associated with the pathology in MPTP intoxicated mice; 5) to determine the nature and severity of oxidative damage to alpha-Syn and neurofilaments in MPTP intoxicated mice. The results of these studies will provide detained information critical to understanding in vivo pathogenetic relationships between abnormal alpha- synuclein biology and the degeneration/dysfunction of the nigral-striatal dopaminergic system. This information, in concern with availability of Tg mouse models of PD, will provide an in vivo system in which novel therapeutic strategies can be tested.